The cyclin-dependent kinases (CDKs) are a family of serine/threonin protein kinases that play a key role in the regulation of progression through the cell division cycle. Individual CDKs phosphorylate distinct substrates in different phases of the cell cycle and therefore are usually classified as either G1, S, or G2/M phase specific. Regulation of these kinases is tightly controlled at different levels including interactions with negative and positive partners, activation by (de)phosphorylation and subcellular localization. Cell cycle dysregulation, a hallmark of transformed cells is accompanied with altered CDK activity in many cancers, caused either by changed expression or activation of CDKs and their interacting proteins. In particular, CDK2 and 4 are promising pharmacological targets for novel anticancer agents.
During the past decade, many potent and selective inhibitors of CDKs have been developed in SAR drug discovery programs, in spite of a relevant degree of active site similarity across the realm of protein kinases. Generally, CDK inhibitors comprise structurally distinct flat heterocyclic molecules, entering the active site and competing with ATP, a feature usually demonstrated by enzyme kinetic assay and inhibitor-CDK2 co-crystal analysis. Anti-CDK drugs possess prominent inhibitory properties against tumor cells both in vitro and in vivo and some of them (e.g. flavopiridol and roscovitine) are already under evaluation in clinical trials as new generation anticancer chemotherapeutics.
Proliferative disorders such as cancer are recognised as diseases of the cell cycle. It has been found that in tumour cells, the mechanisms that normally function to restrain cell division are defective, whilst those that promote division become more active. Cell-cycle regulatory compounds are pivotal in the modulation of abnormal cellular proliferation as they provide ideal therapeutic targets for a range of proliferative disorders.
The present invention seeks to provide new therapeutic compounds. More specifically, the invention relates to compounds that have broad therapeutic applications in the treatment of a number of different diseases and/or that are capable of inhibiting one or more protein kinases. In particular, the invention seeks to provide compounds having improved selectivity and efficiency index, i.e. that are less toxic and more efficacious than analogues known heretofore.